1. Field of the Invention
The present invention relates to novel thiazoline acids and derivatives thereof useful as chelators of trivalent metals in therapeutic applications.
2. Discussion of the Prior Art
While many organisms are auxotrophic for Fe (III), because of the insolubility of the hydroxide (Ksp=1xc3x9710xe2x88x9238, [Acc. Chem. Res., Vol. 12, Raymond et al, xe2x80x9cCoordination Chemistry and Microbial Iron Transport,xe2x80x9d pages 183-190 (1979)]; formed under physiological conditions, nature has developer rather sophisticated iron storage and transport systems. Microorganisms utilize low molecular weight ligands, siderophores, while eukaryotes tend to utilize proteins to transport iron, e.g., transferrin, and store iron, e.g., ferritin [Trends in Biochem. Sci., Vol. 11, Bergeron, xe2x80x9cIron: A Controlling Nutrient in Proliferative Processes,xe2x80x9d pages 133-136 (1986)].
Iron metabolism in primates is characterized by a highly efficient recycling process with no specific mechanism for eliminating this transition metal [Clin. Physiol. Biochem., Vol. 4, Finch et al, xe2x80x9cIron Metabolism,xe2x80x9d pages 5-10 (1986); Ann. Rev. Nutri., Vol. 1, Hallberg, xe2x80x9cBioavailability of Dietary Iron in Man,xe2x80x9d pages 123-147 (1981); N. Engl. J. Med., Vol. 306, Finch et al, xe2x80x9cPerspectives in Iron Metabolism,xe2x80x9d pages 1520-1528 (1982); and Medicine (Baltimore), Vol. 49, Finch et al, xe2x80x9cFerrokinetics in Man,xe2x80x9d pages 17-53 (1970)]. Because it cannot be effectively cleared, the introduction of xe2x80x9cexcess ironxe2x80x9d into this closed metabolic loop leads to chronic overload and ultimately to peroxidative tissue damage [The Molecular Basis of Blood Diseases, Seligman et al, xe2x80x9cMolecular Mechanisms of Iron Metabolism,xe2x80x9d page 219 (1987); Biochem. J. Vol. 229, O""Connell et al, xe2x80x9cThe Role of Iron in Ferritin- and Haemosiderin-Mediated Lipid Peroxidation in Liposomes,xe2x80x9d pages 135-139 (1985); and J. Biol. Chem., Vol. 260, Thomas et al, xe2x80x9cFerritin and Superoxide-Dependent Lipid Peroxidation,xe2x80x9d pages 3275-3280 (1985)]. There are a number of scenarios which can account for xe2x80x9ciron overload,xe2x80x9d e.g., high-iron diet, acute iron ingestion or malabsorption of the metal. In each of these situations, the patient can be treated by phlebotomy [Med. Clin. N. Am., Vol. 50, Weintraub et al, xe2x80x9cThe Treatment of Hemochromatosis by Phlebotomy,xe2x80x9d pages 1579-1590 (1966)]. However, there are iron-overload syndromes secondary to chronic transfusion therapy, e.g., aplastic anemia and thalassemia, in which phlebotomy is not an option [Iron in Biochemistry and Medicine, Vol. II, Hoffbrand, xe2x80x9cTransfusion Siderosis and Chelation Therapy,xe2x80x9d page 499 (London, 1980)]. The patient cannot be bled, as the origin of the excess iron is the transfused red blood cells; thus, the only alternative is chelation therapy. However, to be therapeutically effective, a chelator must be able to remove a minimum of between 0.25 and 0.40 mg of Fe/kg per day [Semin. Hematol., Vol. 27, Brittenham, xe2x80x9cPyridoxal Isonicotinoyl Hydrazone: An Effective Iron-Chelator After Oral Administration,xe2x80x9d pages 112-116 (1990)].
Although considerable effort has been invested in the development of new therapeutics for managing thalassemia the subcutaneous (sc) infusion of desferrioxamine B, a hexa-coordinate hydroxamate iron chelator produced by Streptomyces pilosus [Helv. Chim. Acta, Vol. 43, Bickel et al, xe2x80x9cMetabolic Properties of Actinomycetes. Ferrioxamine B,xe2x80x9d pages 2129-2138 (1960)], is still the protocol of choice. Although the drug""s efficacy and long-term tolerability are well-documented, it suffers from a number of shortcomings associated with low efficiency and marginal oral activity.
Although a substantial number of synthetic iron chelators have been studied in recent years as potential orally active therapeutics, e.g., pyridoxyl isonicotinoyl hydrazone (PIH) [FEBS Lett., Vol. 97, Ponka et al, xe2x80x9cMobilization of Iron from Reticulocytes: Identification of Pyridoxal Isonicotinoyl Hydrazone as a New Iron Chelating Agent,xe2x80x9d pages 317-321 (1979)], hydroxypyridones [J. Med. Chem., Vol. 36, Uhlir et al, xe2x80x9cSpecific Sequestering Agents for the Actinides. 21. Synthesis and Initial Biological Testing of Octadentate Mixed Catecholate-hydroxypyridinonate Ligands,xe2x80x9d pages 504-509 (1993); and Lancet, Vol. 1, Kontoghiorghes et al, xe2x80x9c1,2-Dimethyl-3-hydroxypyrid-4-one, an Orally Active Chelator for the Treatment of Iron Overload,xe2x80x9d pages 1294-1295 (1987)] and bis(o-hydroxybenzyl)-ethylenediaminediacetic acid (HBED, analogues [Ann. N.Y. Acad. Sci., Vol. 612, Grady et al, xe2x80x9cHBED: A Potential Oral Iron Chelator,xe2x80x9d pages 361-368 (1990)], none has yet proven to be completely satisfactory. Interestingly, the siderophores have remained relatively untouched in thin search. Their evaluation as iron-clearing agents has not at all paralleled the rate of their isolation and structural elucidation. In fact, until recently, beyond DFO, only two or some 100 siderophores identified have been studied in animal models: enterobactin [Gen. Pharmac., Vol. 9, Guterman et al, xe2x80x9cFeasibility of Enterochelin as an Iron-Chelating Drug: Studies with Human Serum and a Mouse Model System,xe2x80x9d pages 123-127 (1978)] and rhodotorulic acid [J. Pharmacol. Exp. Ther., Vol. 209, Grady et al, xe2x80x9cRhodotorulic Acid-Investigation of its Potential as an Iron-Chelating Drug,xe2x80x9d pages 342-348 (1979)]. While the former was only marginally effective at clearing iron, the latter compound was reasonably active. Unfortunately, both of these cyclic siderophores exhibited unacceptable toxicity, and neither possessed any oral activity. They were abandoned as there were any number of synthetic chelators with equally unsatisfactory properties from which to choose.
U.S. patent application Ser. No. 08/624,289 filed Mar. 29, 1996, the entire contents and disclosure of which are incorporated herein by reference, discloses certain 2-pyridyl-xcex942-thiazoline-4-carboxylic acids and derivatives thereof useful for the treatment of human and non-human animals in need of therapy entailing the prevention of deposition of trivalent metals and compounds thereof in their tissues, as well as the elimination of such metals and compounds from biological systems overloaded therewith.
It is an object of the present invention to provide additional novel thiazoline acids and derivatives thereof which, because of different volumes of distribution in patients and different lipophilicities than the derivatives of the prior art, provide the ability to control the pharmacokinetic properties and toxicities of the drugs.
Another object of the present invention is to provide novel pharmaceutical compositions for and methods of treatment of human and non-human animals in need of therapy entailing the prevention of deposition of trivalent metals and compounds thereof in tissues thereof, as well as the elimination of such metals and compounds from systems overloaded therewith.
The above and other objects are realized by the present invention, one embodiment of which comprises compounds of the formula: 
wherein: Z is CH or N;
R is H or acyl;
R1, R2, R3 and R5 may be the same or different and represent H, alkyl or hydrocarbyl arylalkyl having up to 14 carbon atoms; and
R4 is H or alkyl having 1-4 carbon atoms;
a salt thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof.
Another embodiment of the invention relates to pharmaceutical compositions in unit dosage form comprising a therapeutically effective amount of the above compound and a pharmaceutically acceptable carrier therefor.
An additional embodiment of the invention concerns methods of preventing or treating a pathological condition in a human or non-human animal that is associated with an excess of a trivalent metal, ion or compound thereof comprising administering to the animal a therapeutically effective amount of the compound defined above.